It is not known which factors are responsible for maintaining ventricular fibrillation (VF): functional factors such as the nonuniform dispersion of refractoriness, action potential dispersion (APD) restitution, conduction velocity (CV) restitution, calcium cycling, and cardiac memory and anatomic factors such as coronary blood vessels, papillary muscles, Purkinje fibers, and myofiber orientation. The roles of these factors may differ (1) during different temporal stages of VF, (2) in different species, (3) with heart disease, and (4) in the presence of pharmacological agents. The goal of this competing renewal application is to answer important questions about which of these factors are most important in maintaining different types of VF. The proposed experiments use intramural and epicardial electrical recordings, a floating microelectrode recording, and, newly developed in our laboratory, intramural optical recordings in pigs and dogs to accomplish 4 specific aims. Specific Aim 1: Ascertain the determinants of APD variability and conduction block during VF. Specific Aim 2: Ascertain the role of Purkinje fibers in maintaining VF. Specific Aim 3: Ascertain the role of coronary vessels in causing block and reentry during VF. Specific Aim 4: Ascertain the role of papillary muscles in causing block and reentry during VF. Accomplishment of these specific aims will furnish the building blocks required to synthesize a global understanding of the complex, multifaceted question of how VF is maintained and how these factors are altered in different cardiac regions, during different temporal stages of VF, in different species, and in the presence of cardiac disease or pharmacologic agents. This understanding will give us new information needed to develop therapies to counteract these mechanisms of VF maintenance to prevent sudden cardiac arrest, one of the leading health problems in the world today.